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BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.This is an article from the symposium: Risks and benefits of Extremely Low LDL Cholesterol.

Clinical guidelines should be based on the best available evidence and are of great importance for patient care and disease prevention. In this respect, the 2013 American College of Cardiology/American Heart Association report is highly appreciated and well-recognized. The report included critical questions concerning hypercholesterolaemia, but its translation into a clinical guideline initiated intense debate worldwide because of the recommendation to switch from a treat-to-target approach for low-density-lipoprotein-cholesterol to a statin dose-based strategy.

Mounting evidence supports the hypothesis that functional foods containing physiologically-active components may be healthful. Longitudinal cohort studies have shown that some food classes and dietary patterns are beneficial in primary prevention, and this has led to the identification of putative functional foods. This field, however, is at its very beginning, and additional research is necessary to substantiate the potential health benefit of foods for which the diet-health relationships are not yet scientifically validated. It appears essential, however, that before health claims are made for particular foods, in vivo randomized, double-blind, placebo controlled trials of clinical end-points are necessary to establish clinical efficacy. Since there is need for research work aimed at devising personalized diet based on genetic make-up, it seems more than reasonable the latter be modeled, at present, on the Mediterranean diet, given the large body of evidence of its healthful effects. The Mediterranean diet is a nutritional model whose origins go back to the traditional dietadopted in European countries bordering the Mediterranean sea, namely central and southern Italy, Greece and Spain; these populations have a lower incidence of cardiovascular diseases than the North American ones, whose diet is characterized by high intake of animal fat. The meeting in Naples and this document both aim to focus on the changes in time in these two different models of dietary habits and their fall out on public health.

Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

Context The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. Objective To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. Design, Setting, and Participants Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). Main Outcome Measures Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low ( = 20%) risk. Results The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A(2) mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A(2) mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. Conclusion In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction. JAMA. 2012; 307(23):2499-2506 www.jama.com

Resume Les atouts de la pomme de terre declinee sous ses nombreuses formes, auxquels s’ajoutent ses qualites nutritives et son faible cout, expliquent sa consommation importante en Occident. Il apparait indispensable de reflechir a la place et au role tenu par la pomme de terre dans le cadre d’un regime alimentaire sain, au vu de l’incidence croissante des maladies cardiometaboliques comme l’atherosclerose, l’obesite et le diabete, tres liees a l’alimentation et au mode de vie. Il est delicat, dans le cadre d’etudes menees sur l’homme, de distinguer le role specifique d’un aliment de base par rapport a un autre. Des travaux indiquent toutefois que les pommes de terre possedent des proprietes interessantes du point de vue cardiovasculaire, notamment en raison de leur faible densite calorique, de leur index glycemique acceptable (en particulier lorsque l’amidon presente une structure complexe, entrainant une digestion lente), de leur teneur elevee en mineraux et en vitamines, et de la presence d’antioxydants, qui ramenes a la consommation de pommes de terre font d’elle l’une des principales sources d’antioxydants d’origine vegetale dans le regime alimentaire americain (vitamine C, vitamine E, carotenoides, selenium et polyphenols). Une etude menee sur les maladies inflammatoires chroniques a revele l’existence d’une association protectrice entre la consommation de pommes de terre chez les hommes et le risque de deces lie a une inflammation. Les resultats d’etudes actuelles preconiseraient l’incorporation des pommes de terre dans le regime des patients diabetiques et dans les recommandations alimentaires pour la prevention du diabete. On dispose de peu d’informations concernant l’effet des frites, l’un des principaux modes de preparation de la pomme de terre en Amerique du Nord, sur les marqueurs des maladies cardiometaboliques, et des etudes controlees randomisees s’avereraient tres utiles pour mieux comprendre cet aliment populaire.

Navzdory soucasným standardům lecby zaměřene na dosaženi cilových hodnot LDL cholesterolu, krevniho tlaku a glykemie maji pacienti s dyslipidemii vysoke rezidualni riziko vzniku vaskularnich přihod. Aterogenni dyslipidemie, zejmena vyssi hodnota triglyceridů a nizka koncentrace HDL cholesterolu, se casto vyskytuje spolu s vyssi koncentraci apolipoproteinu B a non‑HDL cholesterolu u pacientů s diagnostikovanými kardiovaskularnimi onemocněnimi, diabetes mellitus 2. typu, obezitou nebo metabolickým syndromem a je spojena s rezidualnim makrovaskularnim a mikrovaskularnim rizikem. Residual Risk Reduction Initiative (R3i) byla založena proto, aby se touto důležitou problematikou zabývala. Cilem tohoto souhrnneho přehledu je vyzdvihnout skutecnost, že se aterogenni dyslipidemie podili na rezidualnim makrovaskularnim riziku a mikrovaskularnich komplikacich, a doporucit lecebnou intervenci vedouci ke sniženi tohoto rizika, podpořenou důkazy a odborným konsensem. Důležitým prvnim krokem je uprava životniho stylu. Casto je mimo to nutna take farmakoterapie. Přidani niacinu, fibratu nebo ω‑3 mastných kyselin k terapii statiny zlepsuje vsechny lipidove rizikove faktory. Klinicke studie hodnoti, zda maji tyto strategie lepsi klinický přinos než lecba statiny. Zavěrem lze řici, že iniciativa R3i zdůrazňuje potřebu ovlivnit vysokou miru rezidualniho vaskularniho rizika u pacientů s dyslipidemii, kteři jsou leceni prostřednictvim upravy životniho stylu anebo farmakoterapii v souladu se soucasnými standardy lecby.

Esterification of plasma free cholesterol is mediated by lecithin:cholesterol acyl transferase (LCAT). The free cholesterol of plasma high density lipoproteins (HDL) is considered to be the preferred substrate for LCAT. It therefore appeared as a paradox that plasma cholesterol esterification, both in vivo and in vitro, is normal in fish eye disease and Tangier disease, two familial conditions with extremely low plasma HDL levels. Fish eye disease plasma, however, was shown to have LCAT activity primarily acting on combined very low (VLDL) and low (LDL) density lipoproteins, denominated beta-LCAT, while it lacked LCAT activity esterifying HDL cholesterol (alpha-LCAT). Here we show that Tangier plasma, in contrast, has both alpha- and beta-LCAT. Thus, in both fish eye and Tangier diseases it is beta-LCAT that explains the apparent normal plasma cholesterol esterification. We also show that Tangier plasma, having alpha-LCAT activity, normalizes the low cholesteryl ester content as well as the abnormally small size of fish eye disease HDL particles during incubation.

Many measures have been proposed to summarize the prognostic ability of the Cox proportional hazards (CPH) survival model, although none is universally accepted for general use. By contrast, little work has been done to summarize the prognostic ability of the stratified CPH model; such measures would be useful in analyses of individual participant data from multiple studies, data from multi-centre studies, and in single study analysis where stratification is used to avoid making assumptions of proportional hazards. We have chosen three measures developed for the unstratified CPH model (Schemper and Henderson's V , Harrell's C-index and Royston and Sauerbrei's D), adapted them for use with the stratified CPH model and demonstrated how their values can be represented over time. Although each of these measures is promising in principle, we found the measure of explained variation V very difficult to apply when data are combined from several studies with differing durations of participant follow-up. The two other measures considered, D and the C-index, were more applicable under such circumstances. We illustrate the methods using individual participant data from several prospective epidemiological studies of chronic disease outcomes.

BACKGROUND: Statins have been suggested to improve cardiac function, but the evidence underlying beneficial effects of statins in heart failure (HF) is insufficient. We analyzed plasma N‐terminal prohormone brain natriuretic peptide (NT‐proBNP) levels and cardiac function in patients with HF of various etiologies, and who were treated with or without statins. HYPOTHESIS: Statin treatment is associated with improved cardiac function in HF. METHODS: The study cohort consisted of 139 consecutive male patients receiving atorvastatin (n = 44), simvastatin (n = 29), pravastatin (n = 19), or no statin (n = 47). The NT‐proBNP levels were measured using electroluminescence immunoassay. Left ventricular end‐diastolic diameter (LVEDD), fractional shortening (FS), and ejection fraction (EF) were determined by echocardiography. RESULTS: Patients receiving atorvastatin presented with reduced NT‐proBNP levels (1,552 ± 3,416 versus 3,771 ± 6,763 pg/mL; p < 0.01), and improved values of LVEDD (65.2 ± 8.9 versus 70.7 ± 10.9 mm; p < 0.05) and EF (33.2 ± 12.6 versus 28.2 ± 9.6%; p < 0.05). By contrast, plasma NT‐proBNP and cardiac parameters in patients treated with statins other than atorvastatin did not significantly differ from control. Atorvastatin treatment was equally effective in patients with ischemic and nonischemic HF. CONCLUSIONS: Atorvastatin treatment is associated with improved cardiac function in HF, and may represent an additional option for patients with this disease. Copyright © 2008 Wiley Periodicals, Inc.

Objectives— High-density lipoprotein (HDL) levels are inversely proportional to the risk of atherosclerosis, but mechanisms of HDL atheroprotection remain unclear. Monocyte chemoatractant protein-1 (MCP-1) constitutes an early component of inflammatory response in atherosclerosis. Here we investigated the influence of HDL on MCP-1 production in vascular smooth muscle cells (VSMCs) and rat aortic explants. Methods and Results— HDL inhibited the thrombin-induced production of MCP-1 in a concentration-dependent manner. The HDL-dependent inhibition of MCP-1 production was accompanied by the suppression of reactive oxygen species (ROS), which regulate the MCP-1 production in VSMCs. HDL inhibited NAD(P)H oxidase, the preponderant source of ROS in the vasculature, and prevented the activation of Rac1, which precedes NAD(P)H-oxidase activation. The HDL capacity to inhibit MCP-1 production, ROS generation, and NAD(P)H-oxidase activation was emulated by sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), two lysosphingolipids present in HDL, but not by apolipoprotein A-I. HDL-, S1P-, and SPC-induced inhibition of MCP-1 production was attenuated in VSMCs pretreated with VPC23019, an antagonist of lysosphingolipid receptors S1P 1 and S1P 3 , but not by JTE013, an antagonist of S1P 2 . In addition, HDL, S1P, and SPC failed to inhibit MCP1 production and ROS generation in aortas from S1P 3 - and SR-B1-deficient mice. Conclusion— HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent ROS generation and MCP-1 production in a process that requires coordinate signaling through S1P 3 and SR-B1 receptors.

We aimed (1) to construct a modified PROCAM risk algorithm, which incorporates BMI/waist circumference in a model for predicting coronary events; (2) to evaluate how accurate this and the previously established PROCAM risk algorithm predict coronary risk in individuals with metabolic syndrome. Prospective Cardiovascular Munster (PROCAM) Study, a prospective study of men and women at work in the northwest of Germany. A total of 7134 men aged 35–65 years at study entry. On the basis of 404 major coronary events (defined as nonfatal MI and coronary deaths), which occurred within 10 years of follow-up, a modified PROCAM risk algorithm was constructed by incorporating BMI/waist circumference as fixed variable in a Cox proportional hazards model for predicting coronary events. The metabolic syndrome was defined according to the latest recommendations proposed by the NCEP-ATP III Panel. Men who were classified as having the metabolic syndrome (n=2325, prevalence: 32.6%) were 2.59-fold more likely to experience a major coronary event within 10 years of follow-up than men not having the metabolic syndrome. In men with metabolic syndrome, the observed major coronary event rate of 9.6% corresponded well with their estimated global risk according to the modified BMI-based PROCAM risk algorithm (10.2%). Comparative calculations performed with the previously published fully adjusted PROCAM algorithm yielded very similar results. Both PROCAM algorithms provide very accurate means to ascertain coronary risk in male patients with metabolic syndrome.

BACKGROUND AND OBJECTIVE Modern stroke therapy requires patients to correctly identify stroke symptoms and seek immediate hospital admission. US studies showed that only 57% of the population knew at least one stroke symptom. This is the first study about stroke knowledge among German populations. METHODS Using a cross-sectional questionnaire survey, 300 working-age participants of the PROCAM study, the Prospective Cardiovascular Munster Study, and 95 senior citizens of the Augsburg Study, a follow-up project of the MONICA survey 1989/90, were asked about stroke symptoms and what to do if they occur. Good knowledge about stroke was defined as knowing at least two stroke symptoms and calling the emergency medical system or seeking immediate hospital admission in case of symptoms. RESULTS Participation rate in the PROCAM study was 90%, while all senior citizens took part. The mean age of the working population was 41.2 years, the mean age of the retired population was 72.8 years. 35% of the working and 24.5% of the retired participants knew at least two stroke symptoms. Urgent hospital admission was selected by 78.2% of the occupational but only 41.5% of the retired participants. Good stroke knowledge was demonstrated by nearly a third of the workers but less than 10% of the elderly. Among the occupational population, being a white-collar worker or knowing someone with a stroke was a significant predictor of good stroke knowledge. Among senior citizens higher age and current smoking status were significant predictors. CONCLUSION Our study shows significant information deficits about stroke in our population: education needs to be geared especially towards the elderly.

Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10 mg, simvastatin (10-80 mg), and atorvastatin (10-80 mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipo protein [LDL-C] = 145-250 mg/dL; triglyceridesor = 350 mg/dL; N = 975) but without a recent (or = 6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p0.001), whereas statins significantly lowered desmo sterol and lathosterol levels (p0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p0.001).The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe-statin) doses and circulating non-cholesterol levels.

It may be expected that new risk factors emerging from research on biomarkers and SNPs will provide more precise and personalized approaches to prevent and treat cardiovascular disease. They will be particularly useful for a better prognosis in first-degree relatives of patients with major implications on preventive medicine. Most importantly, these new risk factors will lead to better understand why more than 60% of all MIs occur in individuals classified as being at low or intermediate risk according to the currently used risk algorithms. Finally, these fascinating developments have the promising potential to provide new insights into molecular mechanisms leading to atherosclerosis and thus may provide important contributions to the development of highly specific new drugs to treat coronary heart disease, myocardial infarction and stroke.

Objectives— Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1β (IL-1β), a proinflammatory cytokine present in atherosclerotic lesions. Methods and Results— IL-1β-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-κB and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1β signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1β signaling intermediates revealed that NF-κB transactivation was inhibited by apoE in MyD88- and IRAK1- but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1β signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1β signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor-α or polyinosinic:polycytidylic acid. Conclusion— ApoE targets IRAK-1 activation and thereby interrupts IL-1β and IL-18 signaling in VSMCs. This antiinflammatory effect represents a novel antiatherogenic activity of apoE.

Components of the metabolic syndrome such as hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol and obesity have been shown to be associated with increased cholesterol synthesis and reduced cholesterol absorption. In the present study, we measured the lathosterol/cholesterol ratio as an index of cholesterol synthesis and the ratios of cholestanol, campesterol and sitosterol to cholesterol as indices of cholesterol absorption, as well as components of the metabolic syndrome, in 324 men and 168 women from the PROCAM study, an epidemiological study in which raised sitosterol was previously associated with increased coronary risk. Our aim was to determine if the indices of cholesterol synthesis and absorption show a graded relationship with severity of metabolic syndrome.No differences were seen between men and women with regard to the relationship of either the lathosterol/cholesterol or the sitosterol/cholesterol ratios and severity of metabolic syndrome. On multiple regression analysis in men and women together, body mass index showed a positive relationship with the lathosterol/cholesterol ratio (r=0.257, P0.001) and a negative relationship with the sitosterol/cholesterol ratio (r=-0.221, P0.001). HDL-cholesterol showed a negative relationship with the lathosterol/cholesterol ratio (r=-0.166, P=0.001). Triglycerides showed a negative relationship with the sitosterol/cholesterol ratio (r=0.141, P=0.005). Overall, these relationships were graded across quintiles of HDL cholesterol, body mass index and triglyceride and across an index of metabolic syndrome severity (number of components present). Only the cholestanol/cholesterol ratio showed a graded relationship with estimated overall coronary risk.The metabolic syndrome is associated with increased cholesterol synthesis and reduced cholesterol absorption in a relationship that is graded across severity of the individual components of the syndrome and across an index of the severity of the metabolic syndrome as a whole.

Aims To investigate the achievement of treatment goals for low density lipoprotein (LDL) cholesterol in men and women with diabetes mellitus receiving statins in a primary-care setting in Germany. Methods 6,827 men and 5,989 women with diabetes mellitus were recruited from among the 28,200 men and 24,200 women participating in the 4E registry of patients being treated with statins for primary hypercholesterolemia unresponsive to diet and lifestyle. Participants were assessed after 6 weeks and 9 months of statin therapy. Attainment of treatment targets was assessed (i) using individual LDL goals based on each participant's individual level of risk and (ii) based on the 2.6 mmol/L target recommended by current European and U.S. guidelines for persons with diabetes. Results At baseline, patients with and without diabetes mellitus had similar LDL cholesterol levels patients (men: 4.5+/-1 vs. 4.7+/-1 mmol/L, women: 4.7+/-1 vs. 4.9+/-1 mmol/L respectively). The mean drop in LDL cholesterol on statin therapy was similar in men and women with and without diabetes, ranging from 26-27 percent all subgroups. After 9 months of statins, individual LDL goals were achieved by 25% of men and 24% of women with diabetes, while only 16% of diabetic men and 12% of diabetic women achieved the 2.6 mmol/L LDL target. These success rates were similar to those of non-diabetics, including those at high risk, in 4E. Conclusions Patients with diabetes mellitus in 4E responded just as well to statins as patients without diabetes. However, achievement of treatment goals in patients with diabetes was just as poor as in other high-risk groups in the 4E cohort.

The 2 most widely used criteria to diagnose the metabolic syndrome (MS) are those developed by the United States Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) and by the International Diabetes Federation (IDF). A major difference between these 2 sets of criteria is that the IDF places more emphasis on waist circumference. We compared the prevalence of MS using the ATP III and the IDF guidelines in 2 American (the Dallas Health Study and National Health and Nutrition Examination Survey) and 1 German (Prospective Cardiovascular Munster study) population samples. When the ATP III criteria were used, the prevalence of MS was higher in the United States than the German samples in both women (37% vs. 18%) and men (30% vs 25%), whereas when the IDF criteria were used, the prevalence of MS was 25% higher in the German than the American sample. Although in the United States both sets of criteria identified mostly the same people (concordance of about 90%), this was less true in Germany (concordance about 80%). To determine which criteria better predicted adverse cardiovascular outcomes, the incidence of coronary events associated with MS, as defined using the ATP III or the IDF criteria, were compared over a 10-year period among the middle-aged men in the German sample (n = 7,152). A total of 3.4% of men without MS developed an event. A much higher percentage of the men with MS defined by the ATP III criteria (10.7%) than the IDF criteria (5.5%) had a cardiovascular event. In conclusion, although the prevalence of MS was higher when the IDF criteria were used in the German sample, the IDF criteria have lower predictive power for coronary events.

Background— Numerous in vitro studies suggest that sphingosine 1-phosphate (S1P), a bioactive lysosphingolipid associated with high-density lipoproteins, accounts at least partly for the potent antiinflammatory properties of high-density lipoprotein and, thereby, contributes to the antiatherogenic potential attributed to high-density lipoproteins. The present study was undertaken to investigate whether modulation of S1P signaling would affect atherosclerosis in a murine model of disease. Methods and Results— Low-density lipoprotein receptor–deficient mice on a cholesterol-rich diet were given FTY720, a synthetic S1P analogue, at low (0.04 mg/kg per day) or high (0.4 mg/kg per day) doses for 16 weeks. FTY720 dose-dependently reduced atherosclerotic lesion formation, both in the aortic root and brachiocephalic artery, and almost completely blunted necrotic core formation. Plasma lipids remained unchanged during the course of FTY720 treatment. However, FTY720 lowered blood lymphocyte count (at a high dose) and significantly interfered with lymphocyte function, as evidenced by reduced splenocyte proliferation and interferon-γ levels in plasma. Plasma concentrations of proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-6, IL-12, and regulated on activation normal T cell expressed and secreted were reduced by FTY720 administration. Moreover, lipopolysaccharide-elicited generation of nitrite/nitrate and IL-6—two markers of classical (M1) macrophage activation—was inhibited, whereas IL-4–induced production of IL-1–receptor antagonist, a marker of alternative (M2) macrophage activation, was augmented in peritoneal macrophages from FTY720-treated low-density lipoprotein receptor–deficient mice. Conclusions— The present results demonstrate that an S1P analogue inhibits atherosclerosis by modulating lymphocyte and macrophage function, and these results are consistent with the notion that S1P contributes to the antiatherogenic potential of high-density lipoprotein.

There is now mounting evidence that erectile dysfunction (ED) is an early predictor of coronary heart disease (CHD). Men presenting with ED but no other cardiovascular symptoms provide an opportunity for the treating physician to test for asymptomatic CHD and to reduce CHD risk factors.

We investigated the serum phytosterol responses of heterozygous relatives of sitosterolemia patients to diets enriched in phytosterols or stanols.Randomized double-blind crossover design.Muenster, Germany.Eight heterozygous and 13 control subjects were recruited. One heterozygote and three controls dropped out.Seven heterozygotes and 10 controls received daily portions of margarine containing 2 g of plant sterols, 2 g of stanols or a control margarine for 6 weeks each in a randomized order. These phases were intercepted by wash-out periods of 6 weeks each.Compared to the control period, serum phytosterol concentrations increased overall by more than 20% when subjects consumed the plant sterol margarine (F((1,15))=8.719, P=0.01), with no significant difference between heterozygotes (mean +14.5 (s.d. 17.2) micromol/l, +23.0%) and controls (+4.9 (9.9) micromol/l, +20.5%; F((1,15))=2.168, P=0.162), but decreased when subjects consumed the stanol-enriched margarine (F((1,15))=12.124, P=0.003), again to a similar extent in heterozygotes (-34.2 (41.2) micromol/l, -54.2%) and controls (-12.2 (9.2) micromol/l, -50.6%; F((1,15))=2.729, P=0.119). The lowest total serum concentrations of cholesterol and phytosterols were seen after the diet enriched in stanols. Serum stanol concentrations increased on this diet, but on a very low level and never exceeded 0.05% of serum cholesterol levels in any subject.Serum phytosterol concentrations increased only moderately in heterozygotes consuming a diet enriched in phytosterols, indicating that they retained considerable capacity to excrete phytosterols even at higher intakes.

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

The search for genes involved in the pathogenesis of stroke has been highlighted as a field of needs. We followed the concept, that stroke represents a complex genetic disorder, and analyzed the contribution of 106 informative single nucleotide polymorphisms (SNPs) from 63 candidate genes for cardiovascular diseases for the risk of stroke. We conducted two independent case-control studies in two different German regions and recruited a total of 1,901 hospitalized stroke cases and 1,747 regional population controls. The smaller of both studies was used as the replication study. Multiplex PCR in combination with allele-specific hybridization was used for genotype determination. Descriptive statistics, permutations and multivariable logistic regression were used in the analyses. After permutation testing 5 SNPs, located in the nitric oxide synthase 3, the alpha 2 integrin, the interleukin 13, the selectin P and the chemokine receptor 2 genes, had a significant allele difference between cases and controls in the larger study. For one of these SNPs, the glu298asp polymorphism in the nitric oxide synthase 3 gene, an association with ischemic stroke was replicated in the second study and also in a combined analysis of both studies. This association was independent of age, gender, hypertension, diabetes and hypercholesterolemia in both studies. Using large sample sizes and a replication study approach, we found evidence for a role of a polymorphism in the nitric oxide synthase 3 gene in stroke onset.

Improvements in cardiovascular outcomes have occurred in recent decades, but a serious burden of cardiovascular morbidity and mortality remains. Data from large, prospective observational studies, such as the PROspective CArdiovascular Munster (PROCAM) Study, have facilitated the design of simple risk factor scoring systems suitable for the estimation of global cardiovascular risk in routine clinical practice. These systems show that dyslipidaemia remains an important contributor to global cardiovascular risk, despite the increased success in controlling LDL cholesterol in recent years. Data from PROCAM have shown that low HDL cholesterol is prognostically important, especially in patients at high global risk due to the presence of concomitant risk factors and in patients with concomitant low HDL cholesterol and hypertriglyceridaemia. Newer techniques, including neural network analysis, myocardial imaging, and genotyping, are likely to add to the precision with which patients requiring cardiovascular intervention are identified in the future. The management of global cardiovascular risk is based on addressing individual cardiovascular risk factors, including hypercholesterolaemia, low HDL cholesterol, and hypertension. In particular, consideration should be given to correcting low HDL cholesterol by the addition of nicotinic acid or a fibrate to the therapeutic regimen in addition to treatments to control LDL cholesterol.

The ATP-binding cassette transporter ABCG1 mediates the transport of excess cholesterol from macrophages and other cell types to high density lipoprotein (HDL) but not to lipid-depleted apolipoprotein AI. Several splice variants which may have different functions have been identified in mammals. In the current study, we characterized the human splice variant ABCG1(666), which differs from full-length ABCG1(678) by absence of an internal segment of 12 amino acids (VKQTKRLKGLRK). Accordingly spliced ABCG1 transcripts were detected in macrophages and liver in approximately twofold higher amounts than the alternatively spliced ABCG1 form encoding full-length ABCG1. We used transient and stable expression of ABCG1(666) fusion proteins to characterize glycosylation, subcellular localization, molecular interaction and functions of this ABCG1 variant. It could be demonstrated that ABCG1(666) is located at the cell surface and has the ability to form cholesterol transport competent homodimers which affect cellular cholesterol export in a similar manner as previously characterized forms of ABCG1. Our results support that ABCG1(666) may in fact be the most prominent form of functional ABCG1 expressed in the human.

Aims The QT interval in the surface ECG is one of the most often used risk stratifiers in families with congenital long QT syndrome (LQTS). The best ECG lead for clinical management of LQTS families remains unclear. Methods and results The predictive power of the QTc interval in all ECG leads was studied in 200 consecutive genotyped LQTS family members to identify mutation carriers ( n =103; age: 35±19 years) and high-risk LQTS patients ( n =16 with survived sudden cardiac arrest) using receiver operating curve (ROC) analysis (ROC=area under curve). Additionally, the risk for events (syncope and sudden cardiac arrest) was calculated for QTc decile in all individuals. The predictive power was highest in lead II and lead V5 for identifying carriers in LQTS families. These ECG leads were optimal for risk stratification (ROC range 0.83–0.87). In these leads, positive predictive value (PPV) and negative predictive value (NPV) were highest for suggested QTc cut-offs (440 and 500 ms) for identification of LQTS mutation carriers and high-risk patients (PPV between 78–81 and 73–80%, respectively). The risk for events in QTc deciles increased exponentially from 10 to 80% and was 40% for QTc>500 ms. Conclusion On the basis of these data, QTc is the best diagnostic and prognostic ECG parameter in LQTS families. A single measurement should be obtained in lead II if measurable and then in left precordial leads (preferably V5) as a second choice.

Low density lipoproteins (LDL) inhibit the Na+/H+ antiport and thereby sensitize platelet towards agonist. However, mechanisms underlying the suppressing effect of LDL on Na+/H+ exchange are unclear. We here show that the lowering of intracellular pH and the suppression of the sodium propionate-induced Na+/H+ exchange in the presence of LDL are abolished by SKF86002, a selective inhibitor of p38MAP kinase (p38MAPK). The inhibitory effect of LDL on Na+/H+ exchange was mimicked by H2O2, which directly activates p38MAPK. Exposure of platelets to LDL or H2O2 led to phosphorylation of p38MAPK, its upstream regulator MAP kinase kinase 3/6 (MKK 3/6), and its downstream target heat shock protein 27 (HSP27), and this effect was abrogated in SKF86002-pretreated platelets. In addition, both LDL and H2O2 produced the SKF86002-sensitive phosphorylation of an oligopeptide encompassing p38MAPK phosphorylation sequence derived from NHE-1, a major Na+/H+ exchanger in platelets. We further show that the sensitizing effects of LDL on the thrombin-induced platelet activation, as reflected by aggregation and granule secretion, are abolished in cells pretreated with SKF86002. We conclude that activation of p38MAPK is required for the inhibitory effect of LDL on Na+/H+ antiport and thereby for LDL-dependent sensitization in human platelets.

Sitosterolemia, a rare genetic disorder characterized by profoundly elevated plasma sitosterol concentrations, is associated with premature atherosclerosis in some individuals. This study was conducted to evaluate if the modest sitosterol elevations seen in the general population are also associated with the occurrence of coronary events.A nested case-control study using stored samples from male participants in the Prospective Cardiovascular Münster (PROCAM) study was performed. Each of 159 men who suffered a myocardial infarction or sudden coronary death (major coronary event) within 10 years of follow-up in PROCAM was matched with 2 controls (N = 318) by age, smoking status, and date of investigation. Analysis was performed using conditional logistic regression. Plasma sitosterol concentrations were elevated in cases compared with controls (4.94 +/- 3.44 micromol/L versus 4.27 +/- 2.38 micromol/L; P = 0.028). The upper quartile of sitosterol (5.25 micromol/L) was associated with a 1.8-fold increase in risk (P0.05) compared with the lower three quartiles. Among men with an absolute coronary riskor = 20% in 10 years as calculated using the PROCAM algorithm, high sitosterol concentrations were associated with an additional 3-fold increase in the incidence of coronary events (P = 0.032); a similar, significant relationship was observed between a high sitosterol/cholesterol ratio and coronary risk (P = 0.030).Elevations in sitosterol concentrations and the sitosterol/cholesterol ratio appear to be associated with an increased occurrence of major coronary events in men at high global risk of coronary heart disease. Further evaluations are warranted to confirm these preliminary findings.

The "Deutschland SCORE" has low predictive power and greatly overestimates the true risk of coronary heart disease in Germany. Widespread use of this score would lead to massive over-treatment. For this reason, we cannot recommend this score for general use.

Numerous epidemiologic and interventional studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well documented HDL functions that may account for the antiatherogenic effects of this lipoprotein. The best recognized of these is the capacity of HDL to transport cholesterol from the periphery to the liver, and thereby prevent cholesterol deposition in the arterial wall. Further properties of HDL that may also be antiatherogenic include its potent anti oxidative and anti-inflammatory action. In addition, HDL seems to be involved in processes related to senescence at both the cellular and whole-organism level. Both protein components of HDL (such as apolipoprotein A-I) and its lipid components (such as, lysosphingolipids) appear to mediate the antiatherogenic and anti-aging effects of HDL. The purpose of this review is to summarize the novel functions of HDL that may protect from atherosclerosis and senescence.

Numerous epidemiological studies document an inverse relationship between plasma high-density lipoprotein (HDL) levels and the extent of atherosclerotic disease. The atheroprotective effects of HDL are more and more often seen in conjunction with the ability of HDL to restrict proinflammatory processes and thereby to carry out cytoprotection and organoprotection. Lysosphingolipids such as sphingosine 1 phosphate, sphingosylphosphorylcholine, and lysosulfatide are biologically active compounds that have recently been found to be associated with HDL particles. An increasing body of evidence suggests that several anti-inflammatory effects exerted by HDL can be attributed to the presence of lysosphingolipids in this lipoprotein fraction. In this review, we discuss the latest developments concerning the potential atheroprotective role of HDL-associated lysosphingolipids.

The assessment of overall cardiovascular risk is a valuable and accepted means of identifying patients who are likely to benefit most from intervention to control individual cardiovascular risk. A straightforward and accurate means of calculating overall cardiovascular risk has been derived from the PROspective CArdiovascular Munster (PROCAM) Study, a large observational cohort study. The PROCAM risk calculator has several advantages over other risk calculators. For example, the algorithm derived from the Framingham study consistently and markedly overestimates the risk of myocardial infarction in the PROCAM population, or in a German cohort within the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Study, administered by the World Health Organization. In addition, the PROCAM risk calculator incorporates a broader range of commonly measured diagnostic parameters than the Framingham risk calculator. The multivariate Cox proportional hazards model that supports the PROCAM risk calculator has also provided valuable information on the principal driving forces behind atherosclerotic cardiovascular disease, with age, the level of LDL-cholesterol, smoking, the level of HDL-cholesterol, systolic blood pressure, family history of myocardial infarction, diagnosis of diabetes, and triglycerides all making significant contributions. As in other studies, low HDL-cholesterol emerged as a significant and independent risk factor for coronary disease, providing support for strategies aimed at correcting low HDL-cholesterol in addition to those aimed at reducing elevated levels of LDL-cholesterol.

Die Empfehlungen der International Task Force for the Prevention of Coronary Heart Disease/International Atherosclerosis Society (ITF/IAS), des US-amerikanischen Adult Treatment Panel III des National Cholesterol Education Programs (ATP III) und die 3rd Joint European Guidelines (3JE) zur Pravention der Koronaren Herzkrankheit (KHK) stimmen bezuglich der Tertiarpravention gut uberein und empfehlen fur Patienten mit manifester KHK die Senkung des Blutdrucks unter 140/90 mm Hg und des LDL-Cholesterins unter 2,6 mmol/l (100 mg/dl). Die Empfehlungen zur Pravention kardiovaskuarer Ereignisse beim asymptomatischen Hochrisikopatienten (Sekundarpravention) weichen voneinander ab, vor allem bezuglich der zur Risikoeinschatzung angewandten Strategie. Insbesondere die ITF/IAS- und 3JE-Empfehlungen erheben den Anspruch, national in den verschiedenen Landern Europas umgesetzt zu werden. Deshalb verglichen wir die drei Empfehlungen anhand der Daten von mannlichen Teilnehmern der Prospective Cardiovascular Munster (PROCAM)-Studie bezuglich ihrer diagnostischen Qualitaten. Die Empfehlungen der ITF/IAS zeigten die hochste Spezifitat (94,5%), positive pradiktive Wertigkeit (32,0%) und diagnostische Effizienz (90,5%), die 3JE-Empfehlungen die hochste Sensitivitat (64,6%) bei allerdings niedrigster Spezifitat (77,9%), positiver pradiktiver Wertigkeit (17,5%) und diagnostischer Effizienz (77,0%). Bei Anwendung der 3JE-Empfehlungen wurden 25% der deutschen Manner im Alter von 35–65 Jahren als kardiovaskulare Hochrisikopatienten eingeschatzt, bei Anwendung der ITF/IAS-Empfehlungen nur 7,5%. Angesichts knapper Ressourcen im Gesundheitswesen erscheint damit die Entwicklung von deutschen Praventionsempfehlungen auf der Basis der ITF/ IAS-Empfehlungen ratsam.

Objectives. Overproduction of interleukin-10 (IL-10) is a pivotal feature in the pathophysiology of systemic lupus erythematosus (SLE). In vitro IL-10 secretion has previously been related to haplotypes of the IL-10 promoter microsatellite polymorphisms IL10.R and IL10.G. Published data concerning the association of IL10.G alleles with susceptibility to SLE are inconsistent in different ethnic populations. We analysed the association of IL-10 promoter microsatellite polymorphisms with disease susceptibility and manifestations in German Caucasian patients with SLE. Methods. Two hundred and ten (210) SLE patients fulfilling the 1997 revised ACR criteria and 158 ethnically, age- and sex-matched healthy controls were genotyped for the IL-10 promoter microsatellite polymorphisms by fragment length analysis. Haplotypes were reconstructed using a Bayesian coalescent theory-based method with PHASE software. Allele and haplotype distributions were compared between patients and controls and between subgroups of patients with different clinical and immunopathological findings. Results. In the study population no significant associations of individual IL10.R and G alleles or their haplotypes with susceptibility to SLE or major clinical manifestations were observed. By contrast, alleles G14 and G15 and haplotypes R2-G14 and R2-G15 were significantly over-represented in anti-Sm antibody-positive patients. Conclusions. The IL-10 promoter microsatellite polymorphisms and their haplotypes do not constitute a major risk factor for SLE in German Caucasians. However, the identification of genetic markers such as the IL-10 high-response haplotype R2-G14 predisposing for the production of anti-Sm antibodies may help to elucidate the conditions that lead to the development of SLE.

Summary objective IGFs and their binding proteins (IGFBPs) are produced both systemically and locally by cells of the cardiovascular system. As growth promoters, they may play a role in atherosclerosis. design Case–control, cross-sectional. patients A total of 95 nondiabetic male patients with coronary heart disease (CHD) and 92 probands from the Prospective Cardiovascular Munster (PROCAM) who were below the age of 60 years and matched by age, body mass index (BMI) and smoking habits measurements We analysed the strength and independence of associations of angiographically assessed presence of CHD with BMI, systolic and diastolic blood pressure, total, high-density lipoprotein (HDL) and LDL cholesterol, triglycerides, lipoprotein(a), apolipoproteins A-I and B, total and free IGF-I, IGF-II, IGFBP-1, IGFBP-3, IGFBP-5, acid-labile subunit (ALS), insulin, C-peptide, testosterone, DHEAS and sex hormone binding globulin. results Using multivariate statistical analysis, the presence of CHD had significant positive associations with total IGF-I, IGFBP-5, ALS and IGFBP-3. These associations were independent of each other as well as of traditional risk factors, insulin and sex hormones. conclusion These observations may indicate a pathogenetic role of the GH/IGF axis in coronary atherosclerosis.

Ezetimibe belongs to a group of selective and very effective 2-azetidione cholesterol absorption inhibitors which act on the level of cholesterol entry into enterocytes. Recent data indicated that the drug prevents the formation of a heterocomplex consisting of annexin-2 and caveolin-l and leads to specific inhibition of an NPCILI-dependent cholesterol uptake pathway required for uptake of micellar cholesterol into enterocytes. Earlier studies have shown that caveolin-l and annexin-2 are also expressed in human macro-phages and we show in this study that human macrophages express NPC1L1. Moreover in human macrophages, Ezetimibe(SCH58235) and its analogue, SCH354909, are bound to specific cell surface receptors followed by endocytosis via the classical endocytic pathway. SCH58235 had no effect on uptake and/or processing of acetylated LDL (Ac-LDL). In contrast, the compound inhibited uptake of oxidized LDL (Ox-LDL) by -50% in a dose-dependent manner. SCH58235 blocked the lipid-induced induction of LXR/RXR target genes ABCAI, ABCGI, and apolipoprotein E distinctively more effectively in macrophages loaded with Ox-LDL than in those loaded with Ac-LDL. Based on these findings, we presume that the caveolin-l-, annexin-2-, and NPClLI-dependent cholesterol uptake system that is operating in enterocytes may also contribute to class B scavenger receptor-dependent uptake of Ox-LDL in human monocyte-derived macrophages.

ATP binding cassette transporter A1 (ABCA1) is involved in regulation of intracellular lipid trafficking and export of cholesterol from cells to high density lipoproteins. ABCA1 defects cause Tangier disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia. In the present study we have demonstrated that ABCA1 is expressed in human platelets and that fibrinogen binding and CD62 surface expression in response to collagen and low concentrations of thrombin, but not to ADP, are defective in platelets from Tangier patients and ABCA1-deficient animals. The expression of platelet membrane receptors such as GPVI, alpha2beta1 integrin, and GPIIb/IIIa, the collagen-induced changes in phosphatidylserine and cholesterol distribution, and the collagen-induced signal transduction examined by phosphorylation of LAT and p72syk and by intracellular Ca2+ mobilization were unaltered in Tangier platelets. The electron microscopy of Tangier platelets revealed reduced numbers of dense bodies and the presence of giant granules typically encountered in platelets from Chediak-Higashi syndrome. Further studies demonstrated impaired release of dense body content in platelets from Tangier patients and ABCA1-deficient animals. In addition, Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers (CD63, LAMP-1, LAMP-2, CD68) during collagen- and thrombin-induced stimulation and by abnormally high lysosomal pH. We conclude that intact ABCA1 function is necessary for proper maturation of dense bodies in platelets. The impaired release of the content of dense bodies may explain the defective activation of Tangier platelets by collagen and low concentrations of thrombin, but not by ADP.

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components including triglyceride-rich lipoproteins (mainly very low-density lipoproteins [VLDL] and VLDL remnants), LDL-C, and lipoprotein(a). The principal features of the atherogenic lipid profile in type 2 diabetes and the metabolic syndrome make them logical targets for nicotinic acid therapy, either alone or in combination with a statin. The lack of comprehensive European data on the prevalence of low HDL-C levels highlights a critical need for education on the importance of raising HDL-C in CHD prevention and treatment. The development of a reliable and accurate assay for HDL-C, as well as clarification of criteria for low and optimal levels of HDL-C in both men and women, constitute critical factors in the reliable identification and treatment of patients at elevated risk of CHD due to low HDL-C. Based on the available evidence, the European Consensus Panel recommends that the minimum target for HDL-C should be 40 mg/dL (1.03 mmol/L) in patients with CHD or with a high level of risk for CHD, including patients at high global risk with type 2 diabetes or the metabolic syndrome.